The Caribbean, Central and South America network for HIV epidemiology (CCASAnet) is an established and productive network within the International epidemiologic Databases to Evaluate AIDS (leDEA) program. CCASAnet was created in 2006 during the first leDEA funding cycle and has brought together clinical, statistical epidemiologic, and informatics resources from HIV clinical care and research sites in Port-au-Prince, Haiti; Mexico City, Mexico; Tegucigalpa, Honduras; Lima, Peru; Buenos Aires, Argentina; Santiago, Chile; and Rio de Janeiro, Belo Horizonte, and Sao Paulo, Brazil, along with a coordinating center in Nashville, USA. Together, the members of the CCASAnet collaboration respond to scientific opportunities arising in the region and across HIV research networks worldwide. The CCASAnet Data Coordinating Center at Vanderbilt University (VDCC) manages the CCASAnet consortium and works to harmonize and analyze the complex databases generated by participating sites. The VDCC also provides mentoring and education to enhance clinical research and data management capabilities at CCASAnet sites, promote junior researchers, and catalyze ongoing growth of scientific leadership in the region. Over the next five years, CCASAnet will evaluate clinical outcomes and complications related to HIV infection and antiretroviral therapy in the region, and determine the impact of infections other than HIV, particularly tuberculosis, hepatitis, human papillomavirus, and dengue. CCASAnet studies will investigate non-communicable diseases such as cancer and heart disease, regional trends in the HIV epidemic and its impact on vulnerable populations, and other issues of public health importance in Latin America. Additionally, studies will address factors uniquely related to children, adolescents, and young adults with HIV. We will continue to develop and apply innovative biostatistics and informatics methods, grow our productive collaborations with other IeDEA regions, and provide leadership in the site assessment and data harmonization initiatives. Through these activities, CCASAnet 3.0 will help advance both the science of HIV epidemiology and the information science that underpins international research collaboration.